Project Summary/Abstract Lysosomal diseases represent more than 70 disorders caused by inherited defects in a spectrum of organellar proteins; they affect many organ systems progressively to cause chronic illness and premature death. The Lysosomal Disease Gordon Research Conference (GRC) has played a crucial role in stimulating discoveries in this field. The 2019 Lysosomal Disease GRC/Gordon Research Seminar (GRS), held at the Hotel Galvez in Galveston, Texas, will offer a critical venue for addressing major topics in lysosomal biology, disease mechanisms, diagnosis and therapy, including (i) lysosomal systems biology, where `big data' is opening the door to genetic and cellular systems at play in the pathophysiology of disease: (ii) innovations in methods that reverse, rather than prevent or stabilize, pathogenesis, a critical advance as many individuals with these disorders come to light long after the pathology is established: (iii) emerging tools to study lysosomal diseases, at the cellular level and in the whole animal; (iv) mechanisms of pathogenesis in disorders that have recently been linked to lysosomal dysfunction; (v) progress in our understanding of lysosome-resident channels, a field that is emerging as critical to ascertaining how various deficiencies impair lysosome function; (vi) lysosome biology; and (vii) advances in clinical approaches focused on lysosomal disease. This conference is unique in the academic calendar and an outstanding complement to other existing lysosomal disease forums in USA and Europe. To address these topics we have invited, as speakers and discussants, 42 scientists and clinicians working in the lysosomal disease and related fields. Importantly, there is a mix of junior and senior investigators from many countries, and we made every effort to include women and minorities. Additionally, we have formatted this year's conference for an additional 12 speakers to be selected from the abstracts, giving us an excellent opportunity to balance the program among junior and senior investigators, women and men, and to encourage minority participants. Of the current program presented in the application, 95% have accepted our invitation. Based on historical data for this conference, we anticipate that approximately one-third of attendees (aside from invited speakers and discussants) will be junior investigators, postdoctoral fellows and graduate students, and all together there will be approximately 160 people focused on lysosome disease, from the science underlying the field to the translation of those findings to patients suffering from lysosomal disease. Finally, the associated GRS insures that the very best and the brightest of the next generation of lysosomal disease researchers will also be integrated within the GRC community. The discussion and cross fertilization of ideas and approaches occurring as part of the GRC and GRS meetings will accelerate our understanding of the role of the lysosomal system in health and in disease and continue to advance the development of effective therapies.